Genomic instability is a general and characteristic feature of both cancer and aging. We are searching for the underlying mechanisms that are responsible for the development of the genomic instability. Replication errors in DNA, telomeric shortening, increased local DNA damage formation, and localized DNA repair defects, are all possible pathways that can lead to genomic instability. Recently, we have found situations where the genomic instability correlated with a deficiency in DNA repair. We are now examining these pathways in human cells from patients with aging or cancer associated genomic instabilities. A good example is hereditary, non-polyposis colorectal carcinoma (HNPCC), where a mismatch DNA repair defect has been found. We now in preliminary studies find a more generalized DNA repair defect in the pathway that repairs bulky DNA lesions, nucleotide excision repair. This will be further characterized and explored in other HNPCC cell lines. In other studies, we find a distinct shortening of the telomeres in cell lines that have mutations or are deficient in the function of the tumorsupressor gene, p53, which then leads to genomic instability.